Diabetes mellitus affects >380 million individuals worldwide and its incidence is increasing at alarming rates. Diabetic retinopathy (DR), the most common complication of diabetes, is the leading cause of new blindness in working-aged persons in the United States. Unfortunately, existing therapies are limited to advanced forms of DR. While therapeutic approaches such as laser photocoagulation, surgical vitrectomy and anti-angiogenic (anti-VEGF) agents treat some of the sight threatening complications, efficacy is inadequate as the disease has already progressed. There is a critical need for therapeutic approaches that act earlier in progression of DR, which would enable the physician to initiate treatment before the onset of visual deterioration. Zietchick Research Institute (ZRI) is investigating a potentially transformative therapeutic approach to addressing early stage DR. Based on work by our group and by others, there is strong support for the role of gonadotropins in upregulating vascular endothelial growth factor (VEGF) levels. High levels of VEGF are strongly associated with the retinal neovascularization that is characteristic of advanced DR. High intraocular VEGF levels have been mainly attributed to retinal ischemia; however, ZRI may have identified another mechanism for retinal VEGF upregulation (independent of hypoxia) via activation of a gonadotropin signaling pathway, that occurs upstream of VEGF production. Thus, targeting gonadotropin receptors may represent a new therapeutic approach for initiating treatment at early stage DR. In this Phase I SBIR proposal, we will assess the feasibility of targeting gonadotropin receptors to provide a DR therapeutic that could be implemented at early DR stage to prevent progression. In particular, we will determine the correlation between intraocular gonadotropin and VEGF levels in vitreous samples (extracted during vitrectomy surgery from diabetic and non-diabetic patients). We will also evaluate whether gonadotropins induces VEGF expression in a human retinal cell line, and furthermore, whether gonadotropin antagonists will inhibit this effect. Upon completion of this Phase I project, we will have demonstrated the feasibility of targeting a hormonal signaling pathway as a new therapeutic approach to addressing DR. In Phase II, ZRI will develop a (non-antibody-based) therapeutic of moderate molecular weight which will allow intraocular penetration. Thus, ZRI's therapeutic would be amenable to convenient and safe modes of administration (e.g., topical eye drop delivery). ZRI's approach has the potential to address the high unmet need for DR therapeutics that act earlier in the disease process before DR has reached its more advanced, vision-threatening form.